The periodontium is a richly innervated tissue that undergoes continuous modelling and remodeling by alveolar bone osteoblasts, osteocytes, and osteoclasts. Studies from our laboratory have demonstrated a close spatial relationship between trigeminal nerve ganglia and the Epithelial Rests of Malassez (ERM), an epithelial cell network residing within the non-mineralized periodontal ligament. Inferior alveolar nerve (IAN) transection studies resulting in dento-alveolar ankylosis and a reduction in ERM have confirmed the essential role of sensory innervation for periodontal homeostasis. For the present application, we have established the IAN transection model in our laboratory and provided radiographic evidence for enhanced mineralization and ankylosis in the periodontal region of rat molars. Gene expression profiling comparing IAN transected and control tissues demonstrated an unexpected 28-fold significant increase in galanin (GAL) and a more than two-fold decrease in the TGF-? signaling molecules Smad2, Smad3 and Tgf-?1, and the Wnt inhibitors Dkk1, Dkk2 and Gsk-3?. In the same IAN transection group, microRNA miR-92b expression was more than two-fold upregulated, as verified via miRNA profiling and RT-PCR. MiR-92b upregulation after IAN transection in conjunction with bioinformatics data implicating Wnt and Tgf-? as possible miR-92b targets prompted us to speculate that GAL affects its skeletogenic downstream effects through miR-92b. In vitro studies revealed that GAL treatment promoted osteogenic differentiation of PDL progenitors and increased mineralization, while reducing osteoclastogenesis of BMMCs. Block of RhoA or application of GAL antagonist affected PDL cytoskeletal organization and gene expression, indicating that GAL functions through G protein coupled receptors. IWhen applied to periodontal pockets of animals suffering from periodontitis, GAL tissue engineering constructs accomplished a 20% increase in alveolar bone levels compared to controls, resulting in a clinically significant increase in alveolar bone height. Based on this promising new set of data we have designed a research plan to define the role of GAL in response to IAN transection, determine the mechanism underlying its effect on skeletogenesis, and exploit its applicability for bone regeneration and the prevention of periodontal ankylosis. The overall goal of our research plan is to test the hypothesis that periodontal nerves affect alveolar bone homeostasis through a GAL?GPCR?miR-92b?TGF-?/Wnt regulatory loop and that application of GAL neurosecretory peptides will stimulate Wnt signaling and new bone formation. We anticipate that the outcomes of our study will lead to innovative neuropeptide based/engineering hybrid approaches that will restore periodontal health in millions of patients and prevent the emotional and functional scars associated with lost teeth and incomplete dentitions.